NM_002440.4:c.2108-856C>T

Variant names:

• chr1-75888395-C-T
• rs3819949
• NM_002440.4:c.2108-856C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002440.4(MSH4):​c.2108-856C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.696 in 151,834 control chromosomes in the GnomAD database, including 37,470 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.70 (37470 hom., cov: 30)
• Consequence: MSH4 NM_002440.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.182
• Publications: 6 publications found

Genes affected

MSH4 (HGNC:7327): (mutS homolog 4) This gene encodes a member of the DNA mismatch repair mutS family. This member is a meiosis-specific protein that is not involved in DNA mismatch correction, but is required for reciprocal recombination and proper segregation of homologous chromosomes at meiosis I. This protein and MSH5 form a heterodimer which binds uniquely to a Holliday Junction and its developmental progenitor, thus provoking ADP-ATP exchange, and stabilizing the interaction between parental chromosomes during meiosis double-stranded break repair. [provided by RefSeq, Aug 2011]

MSH4 Gene-Disease associations (from GenCC):

• premature ovarian failure 20

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.786 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH4	NM_002440.4	c.2108-856C>T		intron_variant	Intron 15 of 19	ENST00000263187.4	NP_002431.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH4	ENST00000263187.4	c.2108-856C>T		intron_variant	Intron 15 of 19	1	NM_002440.4	ENSP00000263187.3

Frequencies

GnomAD3 genomes AF: 0.695 AC: 105506 AN: 151718 Hom.: 37430 Cov.: 30

Gnomad AFR AF: 0.793

Gnomad AMI AF: 0.583

Gnomad AMR AF: 0.736

Gnomad ASJ AF: 0.709

Gnomad EAS AF: 0.313

Gnomad SAS AF: 0.504

Gnomad FIN AF: 0.710

Gnomad MID AF: 0.734

Gnomad NFE AF: 0.667

Gnomad OTH AF: 0.709

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.696 AC: 105605 AN: 151834 Hom.: 37470 Cov.: 30 AF XY: 0.692 AC XY: 51403 AN XY: 74232

African (AFR) AF: 0.793 AC: 32912 AN: 41478

American (AMR) AF: 0.736 AC: 11214 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.709 AC: 2461 AN: 3470

East Asian (EAS) AF: 0.313 AC: 1615 AN: 5160

South Asian (SAS) AF: 0.502 AC: 2412 AN: 4800

European-Finnish (FIN) AF: 0.710 AC: 7441 AN: 10476

Middle Eastern (MID) AF: 0.752 AC: 221 AN: 294

European-Non Finnish (NFE) AF: 0.667 AC: 45299 AN: 67896

Other (OTH) AF: 0.711 AC: 1501 AN: 2110

Alfa AF: 0.700 Hom.: 5190

Bravo AF: 0.705

Asia WGS AF: 0.480 AC: 1660 AN: 3460

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.3
DANN	Benign	0.53
PhyloP100		0.18
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3819949; hg19: chr1-76354080;